2.1 Syntheses of Cryptolepine and Cryptolepine Analogs
Cryptolepine (I), a member of the quindoline family of alkaloids, is among a rare class of natural products whose synthesis was reported prior to its isolation from nature. ##STR1##
Cryptolepine (I) as its hydrogen iodide salt was first synthesized in 1906 by Fichter and Boehringer Fichter, F.; Boehringer, R. Chem. Ber. 1906, 39, 3932! from quindoline (II), which was prepared by treatment of a bis-o-nitrobenzylmalonester with alcoholic sodium hydroxide followed by reduction of the intermediate dihydroxyquindoline derivative with HI/Phosphorous.
Proton and carbon NMR (DMSO-d.sub.6) spectra for cryptolepine were assigned by Tackie et. al Tackie, A. N.;
Sharaf, M. H. M.; Schiff Jr., P. L.; Boye, G. L.; Couch, R. C.; Martin, G. E. J. Heterocyclic Chem. 1991, 28, 1419!; and by Ablordeppy et. al Ablordeppy, S. Y; Hufford, C. D.; Borne, R. F.; Dwuma-Badu, D. Planta Med. 1990, 416, 56.
Only a limited number of analogs of cryptolepine (I) have been synthesized. 5-Methylquindolinium chloride chloride salt of cryptolepine (I)!, 5-methylquindoline cryptolepine (I)!, 7-nitro-5-methylquindolinium chloride, 7-amino-5-methylquindolinium chloride (prepared by iron reduction of 7-nitro-5-methylquindolinium chloride), the free base 7-amino-5-methylquindoline, 11-amino-5-methylquindolinium iodide and its chloride salt, and 11-carboxy-5-methylquindolinium chloride and its methosulphate salt have been prepared by Holt and Petrow or Armit and Robinson (1) Holt, S. J.; Petrow, V. J. Chem Soc. 1948, 919; (2) Armit, J. W.; Robinson, R. J. J. Chem. Soc. 1922, 827!; 5-methyl-10-benzyl-11-benzyloxycarbonyl quindolinium iodide (incorrectly named in literature) has been prepared by Deguitis and Ezyarskaite Deguitis, Y. A.; Ezyarskaite, A. B. Khim. Geterotsik. Soedin. 1986, 1375!; 5-ethylquindolinium iodide was prepared by Fichter and Boehringer Fichter, F.; Boehringer, R. Chem. Ber. 1906, 39, 3932!; and 5,10-dimethyl-11-chloroquindolinium chloride and 5,10-dimethyl-11-N-4-(diethylamino)-1-methyl-1-aminobutyl! quindolinium dichloride have been synthesized by Gorlitzer Gorlitzer, K.; Stockmann, R.; Walter, R. D. Pharmazie 1995, 50, 105!.
The cryptolepine analogs of (I) described above were prepared by alkylation with methyl iodide, ethyl iodide or dimethylsulphate. These procedures require the use of high temperatures, long reaction times and/or the use of high pressure vessels to effect alkylation. These procedures are highly impractical for scale-up purposes and lead to decomposition when the cryptolepine nucleus is functionalized with a variety of groups. ##STR2##
Quindoline (II) had previously been prepared from indigo upon action with base in the presence of a reducing agent followed by decarboxylation with sodium amalgam, and had also been prepared from indigo white in the presence of barium hydroxide and zinc (1) Giraud, E. Compt. Rend. 1879, 89, 104; (2) Giraud, E. Compt. Rend. 1880, 90, 1429; (3) Schutzenberger, P. Compt. Rend. 1877, 85, 147!. In 1910, Fichter and Rohner synthesized quindoline (II) from isatin and indoxyl followed by decarboxylation of the intermediate quindoline-11-carboxylic acid in the presence of KOH/zinc Fichter, F. Rohner, B. Chem. Ber. 1910, 43, 3489!. The procedure for the synthesis of quindoline-11-carboxylic acid was later improved by Holt and Petrow, who used the less-readily oxidizable N-acetyl- and O,N-diacetylindoxyls as starting materials Holt, J. S.; Petrow, V. J. Chem. Soc. 1947, 607!.